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Modified YSK12-MEND-siRNA in Dendritic Cells for Cancer Immunotherapy
Syed S. Alam
Tumors may induce tolerogenesis through signaling dendritic cells to produce tolerogenic molecules, such as indoleamine 2, 3-dioxygenase 1 (IDO1). Tumor-associated immunosuppression is associated with higher mortality in patients. Small interfering RNA (siRNA) has been shown to silence specific target genes in the target cell. The siRNA associated with these genes could support a gene knockdown of these immunosuppressors and reduce mortality. Delivery of these therapeutic nucleic acids is difficult in vivo because siRNA is easily broken down inside the cell and the bloodstream through present nucleases. Use of liposome polymers has been reviewed extensively in literature. YSK12-C4, a lipid nanoparticle developed by Hokkaido University, is a lipid that has both fusogenic and cationic properties, making it ideal for dendritic cell uptake. However, limitations make it less effective in vivo as it may collect in areas other than the target human dendritic cells in the draining lymph node. To improve specific targeting in vivo, ligand-based targeting modifications (anti-DEC205, anti-CD11c, mannose+) and physical targeting (pKa modifications through YSK05 lipid addition) have been proposed to the YSK12-MEND system in order to better target dendritic cells in vivo. In order to estimate the theoretical efficacy of modified YSK12-MEND-siRNA, I investigated prior experiments, both in vivo and in vitro, to recognize the practicality of each modification. In murine hepatocytes, it was found that pKa improved specific uptake in vivo while anti-DEC205 and anti-CD11c peptides were found to be effective in dendritic cells in vivo in mice. Mannose+ lipid nanoparticles were ideal for targeting both dendritic cells and macrophages. These modifications will likely result in an improved uptake, more cell specificity, and transfection efficiency for human dendritic cells.
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The transcription factor Nfe2l2a is required for development of hematopoietic stem cells in the zebrafish embryo
Sivam Bhatt, Teerth Patel, Madeleine Seputro, Anubhav Thapaliya, and Erich Damm
Hematopoietic Stem Cells (HSCs) are the self-renewing population of cells that generate all erythrocytes and leukocytes over the lifetime of a vertebrate organism. HSCs are also the therapeutic units of curative bone marrow transplants used in the treatment of blood malignancies and in gene therapy for genetic blood disorders. In all vertebrate embryos, HSCs originate from the floor of the embryonic dorsal aorta during the endothelial to hematopoietic transition. Nascent HSCs will bud into the blood vessel and be carried to maturation sites by the embryonic blood flow. Despite the curative potential of HSC transplants in blood disorders, this approach is limited by low numbers of immunologically compatible HSCs for transplantation. A major objective is to generate unlimited numbers of patient matched HSCs from patient derived induced pluripotent stem cells (iPSCs) to alleviate this challenge to therapy, however it has not yet been possible to generate HSCs from iPSCs. This is likely because key developmental signals remain unknown. This makes the study of HSC development in the vertebrate embryo a key area of biomedical study. Previous work has suggested glucose metabolism generates reactive oxygen species (ROS) which are needed for HSC development. Nfe2l2a is a transcription factor and master regulator of the cellular antioxidant response and is activated by increased levels of ROS in the cell. Nfe2l2a has been previously indicated as a regulator of ROS mediated cytokine signaling in adult HSCs. Additionally, nfe2l2a is expressed in the embryonic vasculature of zebrafish embryos, which is the origin of HSCs. We sought to determine whether nfe2l2a is required for the development of HSCs in the zebrafish embryo. The zebrafish pre-clinical animal model serves as an appropriate model due to evolutionary conservation of hematopoiesis between the zebrafish and humans. We examined the expression of the conserved hematopoietic markers runx1, cmyb, and rag1 in embryos injected with an antisense morpholino oligonucleotide which disrupts nfe2l2a mRNA translation. We observed a significant reduction in the expression of these markers, indicative of impaired HSC development. Since normal patterning of the embryonic dorsal aorta is required for HSC development, the embryonic vasculature of nfe2l2a morphants was also examined for expression of key marker genes, which indicated normal patterning of these tissues. Interestingly, examination of fli1:EGFP transgenic embryos injected with nfe2l2a morpholino revealed arterio-venous malformations which are indicative of defects in the segregation of the dorsal aorta and cardinal vein. Overall, our work has revealed that nfe2l2a activity is required for the development of HSCs in the zebrafish embryo, possibly by controlling segregation of the dorsal aorta and cardinal vein blood vessels during development. Future experiments will be aimed at determining how nfe2l2a regulates this process.
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The Relationship Between Social Media Use and Depression and Anxiety Symptoms during COVID-19
Tene'sha L. Crews and Christina Sheerin
The rise of the coronavirus (COVID-19) pandemic has caused a global surge in exposure to disaster and crisis-related media. Increases in poor mental health outcomes such as anxiety and depression, are associated with increased exposure to such media content (Abbas et al., 2021; Riehm et al., 2020; Zhao & Zhou, 2020). In recent years, social media has become one of the most widely used sources for news; approximately 48% of adult Americans receive their news from social media (Pew Research Center, 2021). During the COVID-19 pandemic, there has been an increase in social media use due to social distancing and isolation resulting from pandemic-related safety measures (Abbas et al., 2021; Riehm et al., 2020). Further research is needed on the interplay of increased social media use and the associated exposure to crisis-related content, with anxiety and depression symptoms. The current project will investigate these associations by presenting results from an ongoing, longitudinal study, Spit for Science, a yearly series of surveys assessing behavioral health and, more recently, the COVID-19 experiences of undergraduate students. This survey was conducted in May of 2020 on the current active cohort of students shortly after safety precautions were taken to halt on-campus activities (N=897). Participants completed measures assessing COVID-19-related stressors and behaviors and questionnaires assessing anxiety and depression symptoms. Social media use was measured using multiple-item questions assessing the frequency of exposure to COVID-19 related content. Data analysis will be conducted using linear regressions to understand the relationship between the variables of interest. Analyses are currently ongoing. The significance of this study is to contribute to the scientific literature regarding the impact of COVID-19 and social media use on mental health outcomes.
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Development And Usability Testing Of A PHR For Down’s Syndrome (DS) Care Coordination
Jeffrey B. Duah, Elizabeth Baker Ph.D, Bethany Cosgrove Ph.D, and Isosceles Lab
Development and Usability Testing of a PHR for Down’s
Syndrome (DS) Care Coordination
Jeffrey Duah1, UROP Fellow, Dept. of Computer Science, with Dr. Elizabeth Baker1, Dept. of Information Systems, Dr. Bethany Cosgrove2, School of Nursing, and ISOSCELES Lab1
1Virginia Commonwealth University 2UNC Chapel Hill
Parents of children with Down’s Syndrome typically have many health professionals they have to meet with which leads to the need to efficiently document the development of the child. With this, information management becomes a problem for a number of families. Dr. Bethany Cosgrove drafted 321Connect with the purpose of addressing this problem and allowing for smoother coordination of care. This study aims to, 1) create a mHealth application (321 Connect) for documenting the development of children with Down’s Syndrome and 2) conduct usability testing with the general mobile device users on said app. Development for 321Connect (Android) began on February 2021. It was created with an XML front-end, Java for the logic and functionality, and a SQLite database. Usability testing was done via survey through QuestionPro. Users were asked to follow a script and use the app and then fill out a 10-question survey about the usability of the app. Initial results were favorable with the usability score of 78.8 with just 20 participants. Testing is still ongoing and is expected to increase the score. The primary results showed that users agreed that the app was easy to navigate and the systems were well implemented. Users also saw the importance of the app to the Down’s Syndrome community and believed it would greatly benefit them. This is important as this app will be something that caretakers will interact with daily. Ease of use and well-integrated systems are of upmost importance for the success of the app. Dr. Cosgrove’s testing with actual families proved fruitful as they praised the app for its helpfulness and ease of use. With feedback from testing, changes will be made to the prototype in order to provide the families with the best experience possible.
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Dental Safety Net Patients’ Reflections on Their Dental Problems and Opportunities for Care
Jenifer Euceda Nunez
Introduction: Low-income and underserved populations have disproportionately more unmet oral health needs. This may reflect factors across the lifetime as well as current home hygiene and access to care. These experiences lead to dental care having personal impacts on their lives that oftentimes can lead to personal opinions and stories. Their opinions and stories can provide insight to new themes that are not found within the existing limited literature. Steering away from a technical view on oral health research, personal perspectives can provide a new approach to oral health utilization that can further expand the limited existing literature. Objective: To identify findings related to dental safety net patients’ experiences of their oral health and dental care that are not already reflected in the literature. Methods: Using an iterative process, we identified deductive codes from the existing literature on oral health disparities and utilization and inductive codes found within interview recordings and recording transcripts from interviews conducted among participants who obtain services at federally qualified health center (FQHC) in Richmond, Virginia (n=29). This poster explores a new theme not previously well-documented in the literature.
Results: Numerous Latinx patients reflected on their lifetime acceptance of dental problems, their gratitude for treatment opportunities at the FQHC, and the role that their faith has played in their oral health experiences. Discussion: Frameworks and theories need to take into consideration the way patients perceive their oral health experiences, for example through spirituality and cultural methods. Patients have strong cultural beliefs and methods that play a big role in their health and decision-making. Safety net providers should give equal amounts of attention and appropriate care to all patients. Some patients noted that providers wouldn’t give them certain advice or care while others would state the opposite. Fear, as well as low-income, little to no resources, and waiting times for appointments were common reasons why a person might not visit a dentist.
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Comparison of Free versus Encapsulated Drugs on 3T3 Differentiation
Simon H. Friedrich and Gabriel Volpe
The scope of this project was to design, synthesize and test targeted nanoparticles containing hydrophobic and hydrophilic drugs that promote browning in adipose tissue. For hydrophilic drugs the use of liposomes and their hydrophilic core is more useful than the PLGA nanoparticles which have hydrophobic cores. The inhibition of the FOXO1 pathway and modulation of autophagy in adipose tissue can promote browning of white adipose tissue, or an energy burning state where excess energy is burned as heat instead of stored in the cell. If successful, these drugs would offer an alternative treatment for obesity where changes to the patient's lifestyle, such as dieting and frequent exercise, have had little desired effect. The targeted nature of this treatment offers several potential benefits over free drug doses. For example, the FOXO1 pathway interacts with the insulin signal in cells and the inhibition of this pathway in many cell types throughout the body may have various unintended side-effects. Targeted drug delivery using nanoparticles may result in a more efficient transfer of the drug to the adipose tissue and may allow for a lower active drug-load for treatment. We have successfully synthesized PLGA nanoparticles containing AS1842856 and DMPC/DPPC liposomes containing Balfilomycin-A1 or CL316243 using a turbulent jet mixing approach. A targeting peptide, P3 which binds to prohibitin in white adipose tissue vasculature, was conjugated to the PLGA nanoparticles. The particle size, as measured by dynamic light scattering, was found to range between 140-210nm for the PLGA nanoparticles and 90-220nm for the liposomes. We are currently testing the free drugs and nanoparticle encapsulated drugs using the 3T3 cell line. FOXO1 and autophagy inhibitors can prevent differentiation of 3T3 cells into preadipocytes. The 3T3 cells have been successfully differentiated into preadipocytes as measured using oil red O staining and dose response testing is ongoing. The results will demonstrate whether encapsulation and targeted encapsulation improves the response and/or allows for a lower drug dose as compared to the free drug.
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Spanish Translation and Psychometric Validation of a Measure of Acculturative Stress among Latinx Immigrants in the USA
Ria Grover; Kritzia Merced; Chimdindu Ohayagha; Isis Garcia-Rodriguez,; Oswaldo Moreno; and Paul B. Perrin
BACKGROUND: In the U.S., the Latinx community is growing at a faster rate than any other racial and ethnic minority group. Members of this community have been found to experience a number of acculturative stressors after immigrating including xenophobia, racism, and discrimination. Although several scales have been created in recent years to measure acculturative stress in Spanish-speaking immigrants, they are long, do not have nuanced subscales, or have not been validated in an extremely diverse sample of Latinx immigrants.
OBJECTIVE: The purpose of the current study was to translate and psychometrically validate the Riverside Acculturative Stress Inventory (RASI) in a diverse sample of Spanish-speaking immigrants. METHODS: A sample of 202 Latinx immigrants in the U.S. completed the RASI as well as measures of depression and anxiety. RESULTS: An initial confirmatory factor analysis suggested at the overall subscale factor structure was not an ideal fit for the data. Exploratory factor analysis suggested the retention of four subscales, each with three items, forming a 12-item Spanish RASI short form. As indices of convergent validity, the RASI total score was positively associated with depression and anxiety. CONCLUSIONS: Findings from the study contribute to the literature a brief and valid assessment of acculturative stress in Spanish-speaking immigrants. The RASI Spanish short form holds promise to stimulate research on the unique adversities experienced by Latinx immigrants.
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Developing a Model of Aged Decellularized Muscle Matrix with Advanced Glycation Cross-linking
Ammar Jawad, Scott Pennebaker, Lucas C. Olson, Tri M. Nguyen, Barbara D. Boyan, Zvi Schwartz, and Michael J. McClure
Volumetric muscle loss (VML) has been found to overwhelm muscle regeneration, resulting in loss of long-term muscle functionality. Decellularized muscle matrices (DMMs) provide an effective environment for muscle regeneration; however, the age of their source has not been adequately explored for clinical translation. Advanced glycation end-products (AGEs) are chemical cross-links that contribute to the aging process by accumulating on collagen fibers, resulting in a stiffening of the collagenous matrix and an increase in inflammation via the receptor for advanced glycation end-products (RAGE). In previous experiments, we found increased levels of AGE-specific cross-links within DMMs in old mice compared to young as proven by ALT-711 treatment. In this study, we developed a model of aged rat DMMs using AGE cross-links and hypothesized that our AGE-DMM model will contain a higher number of collagen cross-links compared to the control. This AGE-DMM model aims to elucidate the effect of AGEs on muscle regeneration when used in vitro or implanted in a volumetric muscle loss model.
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Mental Health among Chicanos and Chicanas: Barriers to Mental Health Care, Consequences of Disparities, and Resources
Roma A. Kankaria, Shaheer Alam, Ananya Udyaver, and Alyssa Sievers
Mexican Americans, or Chicanos and Chicanas, face many barriers to mental health care. This literature review was conducted by the Collective Corazón—a VCU student organization, mentored by Dr. Indira Sultanić, that addresses Latinx health equity through service and advocacy—in order to examine the underlying causes and consequences of disparities in mental health in Chicanos and Chicanas. Some of the barriers that affect mental health care in Mexican Americans are racial inequities and discrimination, the societal and/or cultural stigma associated with receiving care, language barriers, lack of health insurance, and legal status. Furthermore, among Chicanos, machismo culture is associated with an increased risk for depression and higher stress levels. Colorism has also been correlated with depression among Chicanos with darker skin phenotypes. Cultural identity also plays a role in mental health for Mexican Americans; a balance of Mexican and American culture is associated with a decreased risk for depression. Among Chicanas, there may be justified mistrust of healthcare systems and services due to historical events. The Latina paradox also has unintended health consequences; Latina women are not screened for prenatal depression as often as other ethnic groups. Lastly, are mental health resources for Latinx communities, like Therapy for Latinx and The Focus on You. However, this review argues that in order to reduce the mental health disparities that Chicanos and Chicanas face, there must be increased awareness of the disparities as well as changes in the healthcare system that address current inequities and barriers.
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Health Disparities in Afro-Latinx Populations: Chronic Health Diseases, Linguistic and Cultural Competency, and Inequities and Barriers in Richmond, Virginia
Roma A. Kankaria, Avani Hariprashad, Henzee Machado, Teerth Patel, and Anubhav Thapaliya
Afro-Latinx individuals face health disparities that differ from those faced by white Latinx individuals. This literature review was conducted by the Collective Corazón—a VCU student organization, mentored by Dr. Indira Sultanić, that addresses Latinx health equity through service and advocacy—in order to examine the underlying causes of Afro-Latinx health disparities. Skin color is a predictor of health, life expectancy, and quality of life for many Latinx individuals. On average, Afro-Latinx individuals in particular have less access to education, fewer financial freedoms, and poorer health outcomes. The Afro-Latinx community also describes higher rates of discrimination compared to white Latinx individuals. As a result, Afro-Latinx individuals suffer from higher rates of chronic illness, stress, anxiety, and depression. Furthermore, due to a lower average socioeconomic status and decreased education access that many Afro-Latinx individuals face, the prevalence and incidence of chronic diseases, such as type 2 diabetes, are higher for such populations when compared to national averages. Additionally, COVID-19 has exacerbated inequities and unequal access to resources; chronic comorbidities that Afro-Latinx individuals have are also predictors of poor COVID-19 outcomes. In Richmond in particular, another barrier that affects the health of many Afro-Latinx populations is the lack of access to healthcare services and/or insurance. This review argues that increasing cultural competency and racial equity trainings in healthcare systems, addressing social determinants of health, and encouraging connections with community leaders are ways to reduce health disparities that Afro-Latinx individuals face.
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Man vs Machine: How will Artificial Intelligence and Machine Learning Systems Impact Cancer Diagnosis and the Patient-Physician Relationship?
Aditya Kotha and Faye Prichard
Oncologic diagnosticians are physicians who specialize in interpreting diagnostic exams to diagnose cancer in patients. Software companies have been developing artificial intelligence (AI) systems to interpret these exams to diagnose cancer. These AI systems may affect the traditional role of oncologic diagnosticians if they were to be implemented in the clinical setting. Therefore, I set out to answer my research question: How will AI and machine learning systems impact the roles of oncologic diagnosticians in diagnosing cancer and the patient-physician relationship? By analyzing surveys and studies, I examined the attitudes of oncologic diagnosticians versus cancer patients toward implementing AI systems in healthcare. Furthermore, I compared the diagnosing accuracies of AI systems and oncologic diagnosticians to uncover which screening entity is superior. I also evaluated specific diagnostic workflows to explore the practical implementations of AI systems in oncology. I investigated AI systems’ potential effects on the oncologic patient-physician relationship. Moreover, I reviewed the ethics of utilizing AI systems in cancer diagnostics to determine if AI implementation is practical. I observed positive attitudes amongst oncologic diagnosticians and patients towards the usage of AI systems, especially if these systems are to be used as assistance programs for physicians. In terms of screening accuracy and the impact on patient-physician relationships, studies showed a lack of consensus. There are also several ethical implications present, but policies and guidelines can be implemented to regulate and manage the usage of AI systems as diagnostic tools. In summary, AI and machine learning systems seem unlikely to replace oncologic diagnosticians. Instead, studies suggest that these devices will assist physicians to reduce diagnostic errors and improve accuracy and reliability. The extent to which the patient-physician relationship is influenced by AI systems seems likely to depend on the physician and their style of practice.
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Determining Effective Treatment Regimens for Breast Cancer Using Combined Immunotherapy and Chemotherapy in Vivo
Akhila R. Kunuthuru; Laura Graham; and Harry D. Bear MD, PhD
Breast cancer has the highest incidence rate of all cancers globally in women, and those of African descent, especially West African females, face higher rates of triple-negative breast cancer (TNBC), a more aggressive form of breast cancer. Immunotherapy for breast cancer is a relatively new treatment option, and research is ongoing to identify the best combination treatments for increasing survival of those diagnosed with TNBC. Eganelisib (IPI-549: a PI3K-gamma inhibitor that works to shift M2 macrophages to M1 to augment T cell function) with other combinatory treatments has shown promising results in reducing tumor growth and increasing survival in mice. We have been conducting experiments to determine the most effective treatment regimen that will reduce growth of 4T1 mammary cancers, a murine TNBC model in syngeneic BalbC female mice. Combinations of eganelisib, cyclophosphamide, and anti-PD-1 or anti-PD-L1 have been tested to determine how immunotherapy and chemotherapy can induce a strong immune response, resulting in better responses to chemotherapy. Our current data indicates that a treatment regimen combining eganelisib, cyclophosphamide, and anti-PD-1 was most effective at suppressing tumor growth, compared to other treatments that only included one or two of these treatments. Mean tumor sizes of mice treated with a combination of eganelisib and other treatments were 187±70 mm3, 232±71 mm3, and 227±59 mm3 at the end of the experiments, compared to control data of 576±137 mm3, 414±31 mm3, and 591±200 mm3, respectively. These results could lead to further research on effective immunotherapy treatment combinations for TNBC.
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The Water Solubility of Ursolic Acid Complexes at Different Choline Concentrations
Sera Lim, Renjie Zhan, and Phillip M. Gerk
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Observing Gravitropism in Brassica rapa Roots
Trang Ly, Maya O'Callagham, Lan Poeschl, Adil Saeed, and George Zorn
The objective of this experiment is to observe the effect of gravitropism on the orientation of Brassica rapa (B. rapa) roots. Specifically, amyloplasts that reside at the bottom of root tips act as gravity sensors. As plants are disturbed from upright orientation, roots automatically grow according to the downward pull of gravity. It is hypothesized that as the angle of rotation increases, the angle of root growth is inversely proportional. Five plants containing four seeds of B. rapa were grown over the course of 10 days. Each plates, aside from the control, were rotated once 90°, 80°, and 270° to the horizontal axis. Additionally, one plate contained salted agar at the bottom third to observe the effect of halotropism on root growth. It is hypothesized that as roots approach high salt concentration, they will respond by growing away. Similar to the control, the salted agar plate was kept at 0°. After 10 days, it was observed that the root angle for the 180" rotation was significantly different from the control. The 90° and 270° rotation values differ, but they are within standard ranges of each other. The results showed that the root angle changes in response to increasing plate angle, but they only weakly support the hypothesis that as the angle of rotation of the plates is increased, the root angle inversely decreases.
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Introduction of plasmid DNA into Sneathia vaginalis; the first step to genetic manipulation
Rea Mansukhani, Cathyrn O'Brien, Zion McCoy, and Kimberly K. Jefferson
Many bacterial pathogens are capable of secreting one or more toxins, all of which can be categorized based on their function, target, or mechanism of action. Pore-forming toxins, for instance, are characterized based on their ability to perforate the host membrane. This may result in the delivery of bacterial substances into the host cell, release of compounds from the host cell, and/or death of the host cell. Research from our lab has demonstrated that Sneathia vaginalis, a gram-negative anaerobic bacterial species that is associated with bacterial vaginosis and preterm birth, produces a pore-forming toxin referred to as cytopathogenic toxin A. CptA is capable of lysing human red blood cells and permeabilizing chorionic trophoblasts and other epithelial cells. CptA appears to contribute to the traversal of Sneathia vaginalis across fetal membranes and may therefore contribute towards preterm birth and bacterial vaginosis. In order to confirm its role in fetal membrane traversal, an isogenic mutant of Sneathia vaginalis, in which the cptA gene has been functionally deleted, is needed. To accomplish this, we tested both plasmids and linear PCR products for the ability to insertionally inactivate the cptA gene. If the mutant is no longer able to traverse fetal membranes, then this will confirm that CptA is necessary for the virulence of Sneathia vaginalis.
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COVID-19 Impact and the Association between Sociodemographic, Social Support, Depression, and Anxiety in the Mindful Moms Program
Ashley Nguyen
Background: The Covid-19 Pandemic lockdown resulted in lessened social support and a higher incidence of depressive symptoms in the United States. Low-income families were more likely to have experienced negative impacts on income, access to mental health treatment, stress, and discord within the family, and higher anxiety scores during the pandemic. Minority groups had higher COVID-19 incidence and mortality rates. More than 1 in 5 pregnant women in the United States experience clinically significant depressive symptoms, with marginalized populations carrying a greater burden. Maternal depression is linked to poor maternal and child health outcomes.
Depression scores of pregnant individuals during the pandemic were higher than those who were pregnant before the COVID-19 pandemic. Because of this it is important to understand the association between the impact of COVID-19 and social support, sociodemographic, and mental health among marginalized pregnant women.
Objective: The objective of this study is to examine the association between the impact of COVID-19 sociodemographic (race, age, children, and socioeconomic status), social support, depression, and anxiety.
Methods: Inclusion criteria includes current depressive symptoms (≥7 EPDS); being 12-16 weeks’ gestation at baseline; marginalized status: minorized (Black/Latinx/Native American and other); WIC eligible, and/or low educational attainment (≤high school); ≥18; English language speaking; and absence of suicidal ideation with a plan, psychosis or mania (measured with the MINI). Eligible pregnant women were randomly assigned to treatment or active control groups. Univariate and bivariate analysis were done to assess the differences between participants with high COVID-19 impact and low COVID-19 impact.
Results: The study and my analysis are currently enrolling; the first participant was enrolled mid-September. Currently, the study has enrolled 30 participants. Of the 12 participants with high COVID impact, two-thirds have children and one-third did not and two thirds were between 27 and 35, while one-third was above.
Discussion: COVID-19 and similar disruptors in family life should be studied to understand the impact on women with children.
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Astrocyte Elevated Gene-1 (AEG-1) Deletion Selectively Enhances the Antinociceptive Effects of Morphine
Apurva Puli, Shivani Patel, Bryan Mckiver, Eda Köseli, Devanand Sarkar Ph.D., and M. Imad Damaj Ph.D.
Background: Opioids are a class of drugs that are utilized in clinical settings to alleviate acute and chronic pain, but can often lead to development of tolerance, addiction and overdose following prolonged usage. Opioids such as morphine function by activating endogenous µ opioid receptors, which are located in various tissues throughout the body. Astrocyte Elevated Gene-1 (AEG-1) is a multifunctional protein that regulates inflammation, myeloid cell activity and lipid metabolism. Studies have shown interactions and overlaps in cellular signaling between the inflammatory/immune responses and the endogenous opioid system which could suggest a role for AEG-1 in opioids effects. Our goal is to investigate the role of AEG-1 in morphine mediated pharmacological effects including analgesia. Methods: Adult AEG-1 global knockout (KO) and wild-type (WT) male and female mice (C57BL/6J background) were utilized to assess morphine-induced thermal antinociception (The tail immersion assay test), hyperlocomotion, gastrointestinal (GI) transit inhibition, and tolerance. GI transit was assessed via charcoal transit assay. Locomotor boxes were used to assess spontaneous activity in mice. Results: AEG-1 KO mice displayed increased thermal antinociception following acute and repeated morphine administration compared to their WT counterparts. Pretreatment with naloxone blocked the enhancement of morphine thermal antinociception in AEG-1 KO mice. In addition, chronic morphine treated AEG-1 KO mice displayed reduced morphine tolerance development compared to their WT counterparts. No significant differences in morphine-induced hyperlocomotion or GI transit inhibition were observed between AEG-1 KO and WT mice. Conclusions: Our data suggest that AEG-1 deletion enhances the antinociceptive effects of morphine and reduces tolerance to chronic morphine treatment. However, AEG-1 deletion does not impact morphine-induced locomotor activity of GI transit inhibition. Overall, our results suggest that AEG-1 may function as a modulator of the endogenous opioid system.
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The Association Between Survivors’ Guilt and Gratitude in the Belongingness of First-Generation College Student Refugees
Mehwish Safdar, Chelsea Williams, and Myriam Kadeba
Refugees often experience a lot of stress and trauma before relocating to their host country (Leo, 2021). Additionally, they often continue to experience different challenges while adapting to their new environment (Leo, 2021). Refugees who relocate may experience survivor’s guilt, gratitude to their host country, or may not feel like a member in their new community. On top of new challenges and stressors, refugee students who are the first in their families to attend college feel pressure to excel academically in a way to ‘give back’ to their family and their host country (Turjanmaa & Jasinskaja-Lahti, 2020). Although there has been prior research on refugee individuals, there is limited work focused on first generation refugee college students. The current study aims to test three questions: 1) How does survivors’ guilt impact the feeling of belongingness in first generation college student refugees? 2) Do first generation college student refugees feel obligated to do well in school due to the feeling of indebtedness to their host country and family or the feeling of gratitude? 3) How does gratitude and indebtedness impact the feeling of belongingness in first generation college student refugees? We aim to recruit first generation college refugee students in the United States from multiple colleges to test these research questions. Aims will be tested with questionnaires provided to the students that assesses survivors’ guilt, gratitude, belongingness, obligation, and discrimination. The current abstract will focus on existing literature and the planned study.
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A Highly Conductive, Flexible, and 3D-printable Carbon Nanotube-Elastomer Ink for Additive Bio-manufacturing
Andy Shar, Phillip Glass, and Daeha Joung Ph.D.
The synthesis of a highly conductive, flexible, 3D-printable, and biocompatible ink has been of great interest in the field of bio-based additive manufacturing. Various applications include ultra-sensitive, microscale tactile sensors, patient-customizable scaffolds for cardiac and nerve tissue regeneration, and flexible electrocardiogram (ECG) electrodes. Here, a novel elastomeric carbon nanocomposite is presented consisting of amino-functionalized carbon nanotubes (CNT-NH2) homogenously dispersed in a one-part room-temperature vulcanizing (RTV) silicone matrix. The use of acetone as a swelling solvent aids in electrical percolation through the elastomer matrix. CNT-NH2 ratios can be tuned to fit various needs; higher tensile strength is favored at lower ratios while increased electrical conductivities are observed at greater ratios. Moreover, the fabrication process is facile, inexpensive, and can be conducted at room temperature within the span of minutes, due to the use of acetone as a unique volatile solvent. The resulting ink can be extrusion-printed to yield detailed, flexible, and highly conductive microstructures with resolution up to 250 microns. Future testing of the ink’s biocompatibility is necessary, but its electrical and mechanical properties demonstrate great potential for use in the additive manufacturing of patient-customizable bioelectronics.
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Exploring Cell Differentiation Vs. Localization in Engineered Ligament-to-Bone Entheses
Saagar N. Sheth, Michael E. Brown, and Jennifer L. Puetzer
The anterior cruciate ligament (ACL) connects to bone via structurally complex insertions known as entheses that translate load from elastic ligament and stiff bone via gradients in organization, composition, and cell phenotype [1]. These gradients are not recreated in graft repair or engineered replacements, yielding limited repair options and high failure rates [2]. Previously, we developed a culture system that uses a tensile-compressive interface to guide ligament fibroblasts to develop early postnatal-like entheses by 6 weeks [3]; however, cells used were isolated from the entirety of the neonatal bovine ACL from bone to bone and likely contained multiple cell phenotypes and progenitor cells [3]. This study explored how ligament fibroblasts from ACL mid-substance and fibrochondrocytes from ACL entheses respond to mechanical cues in our system to assess if cells localize to specific tissue regions or remain mixed and differentiate in response to the local mechanical environment over 6 weeks. Confocal microscopy revealed at 0 weeks all regions begin unorganized with an even distribution of ligament (green) and enthesis (violet) cells for 50/50 ligament/enthesis co-culture (Fig 1). By 6 weeks, 50/50 co-culture resulted in early postnatal-like organization [1,3] with mixed cell distribution; however, ligament cells appear to undergo zonal morphological changes with elongated cells in the middle and larger rounded cells under the clamp. Zonal cell morphology, biochemical, and mechanical analysis of 100% ligament, 100% enthesis, and 50/50 co-culture are ongoing.
References: [1] Lu+ 2013, [2] Patel+ 2018, [3] Brown+ 2022.
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Bringing Swipe Out Hunger to VCU: Identifying Best Practices and Analyzing Administrative Policies for Future Reform
Jackie Stephens and Anjali Ta
At first glance, a college campus might look like a place of equal opportunity– communal dorms, shared dining halls, and similar course loads. However, arriving on campus is not where the college access conversation ends if students’ basic needs are not met. Food insecure students are at elevated risk of poor academic performance and delayed degree completion, with first-generation students being particularly vulnerable. Swipe Out Hunger is an organization that partners with colleges to reduce food insecurity among students by allowing those with extra dining hall meal swipes to donate them to food insecure peers. If implemented at VCU, Swipe Out Hunger would mitigate food insecurity amongst the student population by creating a formalized donation process. We analyzed Swipe Out Hunger programs at Florida State University, Sacramento State University, Temple University, Texas A&M, Rutgers University – New Brunswick, UNC Charlotte, and the College of William and Mary. Semi-structured interviews with students, faculty, and staff from each of the chosen universities, alongside an analysis of publicly available information on university, administrative, and contractual policies, informed our creation of an internal roadmap for VCU. Through our findings, best practices were established and an institutional configuration of the program was recommended. As a result, other universities seeking to introduce their own version of a Swipe Out Hunger program will be more knowledgeable about how to achieve successful implementation and ensure long-term sustainability.
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Review of the effects of Asphalt fume emission (VOCs and PAHs) in vitro, in vivo and human studies
Omran Taqi, Nastassja Lewinski, Elham Fini, Eran Rozewski, and Judith Klein-Seetharaman
Review of the effects of Asphalt fume emission (VOCs and PAHs) in vitro, in vivo and human studies
Omran Taqi, Nastassja Lewinski1
1) Department of Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond, VA
Background
Asphalt is abundantly available around human operations including road paving and roofing sites. However, their emissions and fumes (specifically volatile organic compounds (VOCs) and polycyclic aromatic hydrocarbons (PAHs)) have been found to have adverse effects on health. Asphalt fumes are a class 2A carcinogen and exposure can increase the risk of lung cancer, asthma, headache, fatigue, and other cardiovascular diseases.
Methods
We used three literature sources (Google Scholar, PubMed and Web of Science) to gather in vitro, animal in vivo, and human studies about VOCs and/or PAHs exposure, and specifically asphalt/bitumen exposure and their effects on lungs, as well as focusing on biomarker measurements, such as interleukin-8 (IL-8) concentration in blood and 1-hydroxypyrene (1-OHP) in urine samples.
Results
Our review resulted in 80 papers describing various human, in vitro, and in vivo studies. Analyzing the biomarkers reported in these papers revealed that the IL-8 concentration in exposed cells/animals or workers in the asphalt industry is nearly double that of the unexposed control group, and the (1-OHP) concentration in exposed asphalt workers is nearly 11 times the amount of (1-OHP) as the control group.
Conclusions
Due to the limited number of research papers addressing in vitro studies on lung cells (A549 and BEAS-2B cells), future work should focus on developing optimal in vitro asphalt/bitumen exposure conditions for lung cells, as well as developing new technologies that can remove pollutants for people who work in industries with high levels of VOCs or PAHs exposure.
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Deoxyribose phosphate aldolase is required for development of hematopoietic stem cells in the zebrafish embryo
Anubhav Thapaliya, Sanyam Patel, Teerth Y. Patel, Sivam J. Bhatt, and Erich W. Damm
Hematopoietic stem cells (HSCs) are an integral part of modern biomedical research because they are precursors to all blood cell lineages in vertebrates. Further understanding of hematopoietic development will allow for improvements in the success of therapeutic bone marrow transplantation; which is a crucial treatment in management of both malignant and non-malignant blood disorders. Although HSC transplantation is curative for many blood disorders, finding compatible donors is difficult due to a need for immunologic compatibility. Consequently, recent research efforts have been directed towards generating HSCs for the patient, from the patient themselves through the directed differentiation of induced pluripotent stem cells (iPSCs). To achieve this overarching goal, it is imperative to have a thorough understanding of genetics and molecular signals involved in the specification, determination, and differentiation of HSCs during embryonic development so that this process can be replicated using patient derived cells. In all vertebrates, hemogenic endothelium cells, located in the dorsal aorta floor, are the origin of HSCs. Hemogenic endothelial must undergo an endothelial to hematopoietic transition to become HSCs. Oxidative stress, as a result of glycolysis, is required for this transition and to generate proliferating, quiescent, and differentiating HSCs. Deoxyribose phosphate aldolase (Dera) is an enzyme that is involved in controlling the development of stress granules in cells that are under stress. These stress granules are thought to play an important role in mediating the stress response in cells. Dera is expressed in the embryonic vasculature early in zebrafish development – at the time when HSCs first develop. Trunk expression is present in the intermediate cell mass at 18 hours post fertilization (hpf) and in the pronephric ducts, vasculature, and neural crest. Publicly available RNA sequencing data suggests that dera might be somewhat enriched in the hemogenic endothelium. In this study, we knocked down Dera expression in zebrafish embryos by antisense morpholino oligonucleotide and examined expression of the conserved hematopoietic markers: runx1, cmyb and rag1. We found a significant reduction in the expression of these markers, indicating defective HSC development in dera morphant embryos. We further examined the expression of markers of embryonic vasculature development in morphant embryos and found expression to be normal suggesting that defective HSC development was not a result of abnormal vascular patterning. We also conducted drug treatments with cycloheximide and sodium arsenite, at varying concentrations, to determine if embryos are more sensitive to stress in the absence of Dera. In conclusion, normal HSC development requires dera where its role is likely to moderate the cellular stress response to keep it within physiological levels that are required for HSC development.
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Neonatal Blood Methylation Marks Associated with Obstetric Pain Relief
Charles J. Tran, Lin Y. Xie, Christina Hultman, Edwin van den Oord, and Karolina A. Aberg
The placenta, responsible for intrauterine development, can facilitate modifications within the placental epigenome in response to changes in the mother. In turn these changes have the potential to also influence the neonate1. Pain relief during delivery is widely used and frequently involves the use of nitrous oxide (N2O, commonly referred to as laughing gas), and pudendal blocks. These treatments, alone or in combination, are generally accepted as safe methods of providing pain relief to mothers. However, laughing gas and local anesthetics such as the ones used during pudendal blocks have been known to cross the placental barrier from mother to child2,3. Furthermore, although current literature about the effects of laughing gas and pudendal blocks on the epigenome, when used as maternal pain relief, is very limited, some evidence implicates effects of obstetric anesthesia on the neonatal methylome2,4,5. Thus, it is reasonable to hypothesize that obstetric pain relief administered to the mother during childbirth may affect the methylome of the child. In conclusion, we detected methylome-wide significantly associated loci for laughing gas and pudendal block treatment when studied in combination, but not for either of the treatments separately.
Poster presentations from the annual Undergraduate Poster Symposium, organized by the Undergraduate Research Opportunities Program (UROP) and part of VCU Research Week.
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